Lecture_2b_to_post [Compatibility Mode]

Lecture_2b_to_post [Compatibility Mode] - Spontaneous...

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Spontaneous decomposition of DNA: xidation through ‘natural Oxidation through natural processes’ • “The Oxygen Paradox”: oxygen is dangerous for us ven though it is an essential component of energy even though it is an essential component of energy production • defense against oxygen toxicity in mammals is sharp gradient of oxygen tension from environmental level of 20% to 0.5 to 5% oxygen concentration in tissues creasing oxygen tension can lead to DNA damage increasing oxygen tension can lead to DNA damage
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Pathways for intracellular oxidant generation Generation of reactive oxygen species (ROS) via reduction of molecular oxygen e - - uperoxide anion) O 2 + e O 2 (superoxide anion) O 2 - + H 2 O HO 2 (hydroperoxyl radical) HO 2 + e - + H H 2 O 2 (hydrogen peroxide) H 2 O 2 + e - OH - + OH (hydroxyl radical) Endogenous sources of ROS: mitochondria, cytochrome P450, macrophage/inflammatory cells Exogenous sources of ROS: P450 metabolism of certain drugs and toxic compounds such as lindane, TCDD, phenobarbital nvironmental agents can directly contribute to the formation of ROS such as environmental agents can directly contribute to the formation of ROS such as metal ions, chlorinated compounds, radiation. . Cellular antioxidants: Enzymatic : superoxide dismutase, catalase, glutathione peroxidase, glutaredoxin, thioredoxin Nonenzymatic : vitamin E, glutathione, vitamin C, catechins
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Oxidation and compartmentalization of DNA • nucleus is poorly oxygenated intracellular compartment –lacks detectable O 2 metabolism • metabolism of reactive oxygen to mitochondria could be seen as serving to protect nuclear DNA against oxidative DNA damage (evolution?) • but mitochondria also have DNA •w o u l d e x pect that mitochondrial DNA would be more likely to acquire oxidative damage • histones ‘quench’ generation of oxygen radical- inflicted DNA damage, mitochondrial DNA doesn’t have histones
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xidation of DNA bases Oxidation of DNA bases ormation of thymine glycols: formation of thymine glycols: ormation of formamidopyrimidines • formation of formamidopyrimidines • formation of 8-hydroxyguanines. .
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- ydroxyguanine 8 hydroxyguanine oxidation of guanine residues to 8-hydroxyguanine major mutagenic base lesion generated by hydroxyl radicals is 8- ydroxyguanine which base- airs preferentially with denine ther hydroxyguanine, which base pairs preferentially with adenine rather than cytosine : generates transversion mutations after replication cytosine deamination and oxidation of 8-hydroxyguanine are the two major forms of spontaneous directly premutagenic events in living cells both occur at similar frequencies –each type of event takes place 100- 500 times per day in a human cell levels of 8-ohG are higher in mitoDNA than nuclear DNA, and even igher in mitochondria exp to oxidative stress h gher n m tochondr a exp to ox dat e stress
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lkylation damage introduction Alkylation damage introduction • we are exposed to alkylating compounds endogenously and in the environment e.g. exposure to alkylating agents in our food
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Lecture_2b_to_post [Compatibility Mode] - Spontaneous...

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